Cellular immunity is key to our resistance against cancer and chronic infections. Effective cell-mediated immunity requires the participation of dendritic cells (DC), CDS+ T cells (CTL), and CD4+ IFN-gamma- producing type-1 T helper (Thl) cells. CD40L-expressing CD4+ cells are a source of DC-mediated helper signals for the optimal induction and persistence of cytotoxic CD8+ T cell responses. In contrast, it is unclear whether and to what extent the optimal magnitude and the Thl polarization of CD4+ cell responses depend on the feedback signals from CD8+ T cells. Based on our recent observations that human CD8+ T cells activate DC and prime them for high IL-12 production, we hypothesize that at least some populations of CD8+ T cells may provide DC-mediated helper signals for tumor-specific Thl cells and may be utilized to boost the effectiveness of DC -mediated cancer immunotherapy. Defining the role(s) of CD8+ T cells in the development and proper functioning of Thl cells is important for our understanding of the pathology and for the design of immunotherapy in cancer and chronic infections with intracellular pathogens. It may also provide tools to correct the aberrant Th1/Th2 response patterns in autoimmune diseases and allergy. This study will pursue three specific aims: 1. We will analyze the impact of different populations of CD8+ T cells on the ability of DC to provide activating, polarizing, and survival signals for naive and memory CD4+ Th cells. 2. Determine the DCl-polarizing potential of virus-specific and tumor-specific CD8 T cells, and evaluate in vitro the potential for using """"""""heterologous CD8 help"""""""" from virus-specific CD8 T cells to boost the induction of human tumor-specific Thl responses. 3. Determine the roles of virus-specific and tumor-specific CD8+ T cells in the development of Thl-type immunity in vivo, and to use the """"""""heterologous"""""""" CD8 help to boost the induction anti-tumor immunity by DC-mediated vaccination.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095128-04
Application #
7087891
Study Section
Special Emphasis Panel (ZRG1-SSS-H (03))
Program Officer
Howcroft, Thomas K
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$257,773
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Muthuswamy, Ravikumar; Berk, Erik; Junecko, Beth Fallert et al. (2012) NF-ýýB hyperactivation in tumor tissues allows tumor-selective reprogramming of the chemokine microenvironment to enhance the recruitment of cytolytic T effector cells. Cancer Res 72:3735-43
Wieckowski, Eva; Chatta, Gurkamal S; Mailliard, Robbie M et al. (2011) Type-1 polarized dendritic cells loaded with apoptotic prostate cancer cells are potent inducers of CD8(+) T cells against prostate cancer cells and defined prostate cancer-specific epitopes. Prostate 71:125-33
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Wong, Jeffrey L; Mailliard, Robbie B; Moschos, Stergios J et al. (2011) Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells. J Immunother 34:270-8
Kalinski, Pawel; Okada, Hideho (2010) Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors. Semin Immunol 22:173-82
Watchmaker, Payal B; Berk, Erik; Muthuswamy, Ravikumar et al. (2010) Independent regulation of chemokine responsiveness and cytolytic function versus CD8+ T cell expansion by dendritic cells. J Immunol 184:591-7
Kalinski, Pawel; Wieckowski, Eva; Muthuswamy, Ravikumar et al. (2010) Generation of stable Th1/CTL-, Th2-, and Th17-inducing human dendritic cells. Methods Mol Biol 595:117-33
Kalinski, Pawel (2009) Dendritic cells in immunotherapy of established cancer: Roles of signals 1, 2, 3 and 4. Curr Opin Investig Drugs 10:526-35

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